American Indians and Alaska Natives (AI/ANs) face significant drug- and alcohol-related health disparities, particularly in terms of substance use disorder rates and related negative health consequences. The proposed study will consider how one societal-level factor, racial discrimination, may contribute to these disparities, while also examining the protective effects of cultural buffers (i.e., participation in traditional activities traditional spirituality, AI/AN identity). Racial discrimination has been associated with higher rates of substance use among racial/ethnic minority groups (e.g., Pascoe & Smart Richman, 2009; Whitbeck, Hoyt, McMorris, Chen, & Stubben, 2001), and 40% of AI college students report being a victim of overt racial discrimination in the past school year (e.g., called names, harassed; Perry, 2002). Despite the concerning nature of these statistics, the association between discrimination and substance use has not been explored among AI/AN college students, and previous research on discrimination and substance use among AI/ANs has been cross-sectional, thereby precluding causal analyses. The Indigenist Stress-Coping Model (Walters, Simoni, and Evans-Campbell, 2002) posits that cultural buffers temper the positive relationship between discrimination and substance use. To lay the groundwork for culturally-tailored substance use interventions, the proposed study will (1) cross-sectionally and prospectively examine the relationship between discrimination and substance use, and (2) test moderating cultural buffers among AI/AN college students (ages 18-44) attending two post-secondary institutions in a large Southwestern city. In the first part of the study, 343 AI/A students will complete an online questionnaire measuring discrimination, substance use, and cultural buffers. Structural equation modeling will be used to calculate effect sizes for the relationship between discrimination, substance use, and presumed moderators. For the second part of the study, online questionnaire participants who report experiencing discrimination at least a few times a month will be invited to participate in a 21-day daily diary feasibility study measuring discrimination, substance use, and cultural buffers (N=40). Using multi-level modeling, causal links between discrimination and substance use can be explored, and the moderating effects of cultural buffers will also be tested. Findings will contribute to a more nuanced understanding of factors that contribute to health disparities among AI/ANs and lay the groundwork for future prevention and intervention research and clinical efforts. PUBLIC HEALTH RELEVANCE: American Indians and Alaska Natives (AI/ANs) experience significant substance-related health disparities (e.g., high rates of substance use disorders), and discrimination is one societal-level factor that may contribute to these disparities. The proposed study will examine day-to-day relationships between discrimination and substance use and the protective effects of cultural factors (e.g., spirituality) among AI/AN college students, and in so doing, lay the groundwork for culturally-tailored substance use interventions to reduce substance- related health disparities.